This Application PA0 Organ Failure and Nutrition
This application is a continuation-in-part of application Ser. No. 08/826,234 filed Mar. 27, 1997, entitled Nutritional Composition for Improvement of Cell Energetics abandoned.
There are four critical organ systems that are especially likely to fail in aging and critical illness. They are the cardiovascular, central nervous, musculoskeletal and immune systems. We have found that nutrition can be used to prevent or delay the onset of cardiac failure and thereby, promote recovery in disease states affecting the heart. Similar considerations apply to diseases of the other organ systems indicated above.
We have found that the central effect of nutrition in all these systems can be unified into its influence on mitochondrial energetics. That is: inadequate nutitional substrate is a cause of impaired cell energetics. This has led us to invent a composition for the improvement of mitochondrial energetics.
Relationship of malnutrition to mitochondrial function.
Protein-calorie malnutrition contributes to both skeletal and cardiac.sup.1 muscle dysfunction in patients with cardiac failure. Muscle is composed of water, minerals, nitrogen and glycogen.sup.2,3. Feeding wasted individuals results in a gain of the multiple elements in lean tissue.sup.4 including potassium. Body potassium, has been used as an index of body cell mass.sup.5, the metabolically active component of the lean tissue. In contrast to body nitrogen, body potassium responds rapidly to feeding by both oral and intravenous routes.sup.6,7,8,9,10. It has been shown that in malnutrition there is a change in muscle membrane potential resulting in reduced intracellular ionic potassium. The reduced cellular potassium cannot be simply corrected by giving potassium but requires restitution of nutrition. The above mentioned observations suggest that cell ion uptake, an energy dependent process, occurs earlier than protein synthesis during nutritional support. This concept has received experimental support by two studies using .sup.31 P-NMR which showed that malnutrition was associated with a reduced rate of oxidative phosphorylation, suggesting a mitochondrial abnormality.sup.11,12.
Cell energetics are also important for muscle activity and it has been shown.sup.13,14,15,16,17,18,19,20,21,22 that skeletal muscle function, including that of the diaphragm, can be rapidly altered by nutrient deprivation and restored by refeeding. Also the changes in muscle function are specific to alterations in the nutritional status and are not influenced by sepsis, trauma, renal failure and steroid administration.sup.15,17. Christie and Hill indicated that nutritional support improves muscle, including diaphragmatic function before any increase in body protein or body mass.sup.20. Windsor and Hill.sup.21 demonstrated that the functional effects of nutrition are more important than subnormal body protein as an index of surgical risk. Hanning and her colleagues.sup.22 demonstrated the ability of stimulated muscle function as demonstrated by a slow relaxation rate and an altered force-frequency curve to predict the ability of patients with cystic fibrosis to grow as an outcome measure. In contrast, body composition, protein biochemistry, muscle power on an ergometer or use of supplements did not predict growth potential. Among the macronutrients, Castenada et al.sup.23 have shown that protein deficiency can profoundly alter muscle function even when energy intake is sufficient to meet requirements.
The data given above indicate that it is critical to correct protein-calorie malnutrition, with an emphasis on protein repletion, in order to obtain the maximum functional benefits of administering cardiac specific micronutrients. Current diet supplementing strategies for correcting protein-calorie malnutrition focus on giving supplements of protein and energy (carbohydrates and fats). No supplement to date has addressed the cascading series of metabolic abnormalities that can lead to mitochondrial dysfunction. We have shown that in the skeletal muscle protein-calorie malnutrition profoundly reduces mitochondrial oxidative phosphorylation and reduces calcium cycling in cardiac muscle.sup.1.
We have found that there is profound reduction of respiratory chain complex I, II and IV activity in animals given a protein-calorie deficient diet. In addition, complex I activity is similarly reduced in lymphocyte mitochondria showing that these effects are not cardiac specific but apply to mitochondria in other tissues, and protein feeding rapidly restored the abnormality when it was simply due to protein-energy malnutrition (unpublished data).
In addition, certain micronutrients and amino acids also influence mitochondrial function in general. For example, camitine improves mitochondrial DNA transcription and translation in aged animals.sup.24. A specific acyl derivative of carnitine, acetyl-carnitine has been used for mitochondrial DNA synthesis based on findings observed in patients treated with anti-retroviral agents.sup.25. Coenzyme Q can alter immune function.sup.26 and may protect the central nervous system from injury and neurodegeneration.sup.21. On the basis of the above considerations, a nutritional supplement that could maintain or restore mitochondrial function will prevent cardiac failure or aid recovery from cardiac disease. In addition it could also aid in the management of neurodegenerative, musculoskeletal including the muscular abnormality in chronic obstructive lung disease (COPD).sup.16 and immune disorders.
Heart Failure.
Congestive heart failure has emerged as a major health problem during the past two decades. Its morbidity and mortality have shown a steady increase since 1970.sup.28 ; heart failure now affects approximately 1% of the population of the United States and Canada. These data reflect both the aging of our population and the success of modern cardiovascular medicine in converting acute, often previously fatal, cardiac disease into a more chronic process.
The underlying abnormality in congestive heart disease is myocardial dysfunction leading to inadequate blood flow to peripheral tissues. Although there have been considerable advances in our understanding of the pathogenesis of heart failure in recent years, critical questions remain about the evolution of cardiac dysfunction to terminal failure. The importance of elucidating the mechanisms responsible for the evolution of maladaptive hypertrophy to cardiac failure is emphasized by the fact that in spite of our advances, no presently available therapeutic intervention has been shown to substantially improve the long-term survival of patients with dilated cardiomyopathy and congestive heart failure. The underlying heart disease is relentlessly progressive in almost all patients who develop symptoms of overt failure and mortality continues to be unacceptably high; for example, in a recent heart failure trial, SOLVD, 40% of patients in the symptomatic treated group were dead within 4 years.sup.29. Heart transplantation appears to be the only prospect to improve long term survival for many patients.
The reason for this dismal outcome despite modem advances lies in the fact that several metabolic abnormalities have been found in the failing myocardium which together as indicated below result in progressive loss of cardiac myocytes (muscle).
There is a progressive accumulation of calcium in the muscle, which in turn results in increased calcium in the mitochondria. The progressive increase in mitochondrial calcium as well as the basic cardiac disease (ischemic, viral, toxic, genetic) decrease myocyte energy production and increase oxidative stress resulting in free radical damage. The combined result of these three processes promotes myocyte dysfunction and death. In addition these processes also influence skeletal muscle and contribute to fatigue and disability.
The modem pharmacological therapy of heart failure has focused on the amelioration of fluid overload and hemodynamic abnormalities and has not addressed the fundamental fact that if there is progressive loss of cardiac muscle then the patient will inevitably succumb. That is: the inexorable myocyte loss by apoptosis that occurs in heart failure is the key factor responsible for myocardial decompensation and the demise of the patients. Oxidative stress, calcium overload and cellular energy deficiency are well known as principal stimuli for the development of apoptosis.
Among the factors that aggravate myocyte dysfunction there is increasing evidence for the role of nutritional deficiencies both due to reduced intake and to insufficient intake in relation to augmented requirements caused by the underlying disease state, a phenomenon which we will refer to as "conditioned deficiency". In this situation the recommended daily allowances (RDA) do not apply, as requirements may exceed the standard RDA.
The presence of protein-energy malnutrition has been recognized by surveys of hospitalized patients using anthropometric, biochemical and immunologic measures of nutritional status. These surveys have indicated that 50-68% of patients with congestive heart failure were significantly malnourished.sup.31. The proportion of malnourished heart failure patients has been found to be higher than that of patients with cancer, alcoholism or those with acute infection. The cause of protein-energy malnutrition is due to both reduced intake and increased energy demands. Cardiac failure results in a cascade of metabolic effects such as tissue hypoxia, anorexia, hypermetabolism, weakness, dyspnea and hypomotility of the gastrointestinal tract all leading to poor nutrient intake. Anorexia can be aggravated by unpalatable restrictive diets or by converting enzyme inhibitors or by an excess of diuretics, opiates and digitalis. Characteristics of the disease process such as fatigue and early satiety have all been reported in congestive heart failure patients consuming self-selected diets.sup.32,33. These factors lead to compromised food and nutrient intake and subsequently contribute to the poor nutritional status of these cardiac patients. In addition, patients with heart failure have been shown to have significantly increased resting metabolic rates.sup.34,35,36,37 possibly due to the increased work of breathing, fever, cytokines or elevated sympathetic nervous system outflow.
The RDA for the vitamins and related micronutrients recommended by federal nutrition authorities in Canada, the United States and Western Europe (e.g. The Canada Food Guide) are obtained through the analysis of deficiency data in otherwise healthy humans and animals. We have found that with the advent of disease, or due to genetic predisposition, specific metabolic pathways in individual organs and the function of some of these systems alter the nutritional requirements causing conditioned deficiency of both macro-(protein including amino acids, carbohydrates and fats) and micronutrients (electrolytes, trace elements, vitamins and special nutrient substances). Certain pharmaceutical agents or treatment strategies also influence these requirements.
The above considerations indicate that for heart failure and in other conditions detailed below the nutrient intake is instrumental in determining the evolution of tissue damage--its amelioration or acceleration. RDA data, although suitable for a healthy population, are not necessarily appropriate for patients suffering from certain forms of illness or predisposed to sickness through genetic constitution. There is a need for a nutritional supplement that can be taken by persons suffering from illness or with a genetic predisposition to illness.
Musculoskeletal System.
Data given above have clearly demonstrated the relationship of protein deficiency and mitochondrial dysfunction in skeletal muscle. In addition several nutrient agents have been shown to improve skeletal muscle performance. These include creatine, carnitine and taurine.
Central Nervous System.
Mitochondrial dysfunction has been noted as an important factor in several neurodegnerative diseases.sup.38. A central role for defective mitochondrial energy production, and the resulting increased levels of free radicals, in the pathogenesis of various neurodegenerative diseases is gaining increasing acceptance.sup.39.
Immune System.
Immune dysfunction occurs with aging and there is growing evidence that reduced immunity is related to reduced mitochondrial dysfunctions.sup.40.
THE INTERACTING PATHWAYS RESPONSIBLE FOR MITOCHONDRIAL FUNCTION.
We have found that the critical path in these interactions is the flow of energy substrates into the mitochondria through carnitine, the transfer of electrons through the complexes via CoQ10, and the modulation of the calcium pump by taurine. We consider the constituents of this path, namely Carnitine, CoQ10 and Taurine, to be the core constituents required to promote mitochondrial function. We have found that these compounds act together on this critical path to provide a synergistic effect.
The other constituents of the cascade given in FIG. 1 aid the action of this core by modulating oxidative stress which results from external factors and mitochondrial dysfunction and in turn promotes further dysfunction.
Adequate energy production is essential not only for cellular function but also for long term cell survival. Cellular energy production from nutrients, especially fatty acids need the coordinated action of a number of co-factors. Three factors namely, carnitine (critical for the transport of long chain fatty acid substrate), coenzyme Q10 (a key transducer for mitochondrial oxidative phosphorylation), and taurine (a key modulator of calcium accumulation) are important in promoting normal cell energetics.
DETAILS OF ALTERED MITOCHONDRIAL ENERGETICS IN HEART FAILURE.
The data for mitochondrial energetic dysfunction has been clearly documented in heart failure and therefore the following details will focus on heart failure as a paradigm.
In heart failure deficiency of carnitine promotes accumulation of toxic long-chain fatty acids; deficiency of CoQ10 alters electron transport and mitochondrial calcium accumulation also occurs, which can be corrected by the action of taurine. From FIG. 1 it can be seen that normalization of any one of the above three constituents alone will not be sufficient to significantly benefit myocardial energy production in the presence of abnormalities the other factors in the myocardial bioenergetic pathway. In addition, from FIG. 1, it can also be seen that the added action of creatine, known to be deficient in cardiac failure and antioxidants to reduce oxidative stress, known to be elevated in cardiac failure, will enhance the action of the three core constituents carnitine, CoQ10 and taurine. For these constituents to be effective in remodelling the heart, the addition of protein is essential in any supplement. These substances can be given as oral replacements to benefit both myocyte function and long-term survival. Details of the deficiencies and altered metabolism of these constituents in cardiac failure and other diseases are given below. However, it has become apparent that this paradigm applies to a number of other diseases; these will be briefly discussed in each section where appropriate.
REGULATING INTRACELLULAR CALCIUM
The failing myocardium exhibits an increase in calcium content and impaired movement of intracellular calcium. Impaired uptake of calcium adversely affects diastolic relaxation whereas the kinetics of transsarcolemmal calcium flux and calcium release by the sarcoplasmic reticulum is a principal determinant of systolic function. Chronic intracellular calcium overload ultimately leads to cell death.
Taurine:
Metabolism and Physiological Role of Myocardial Taurine.
Taurine (2-aminoethanesulfonic acid) is a unique amino acid, which lacks a carboxyl group, and as such it does not enter into protein synthesis. Taurine appears to be an important amino acid for the modulation of cellular calcium levels, exhibiting a remarkable biphasic action by increasing or decreasing calcium levels appropriate to the maintenance of cellular calcium homeostasis.sup.41,42,43. In the heart, taurine appears to do this by affecting several myocardial membrane systems.sup.41,42,43. It is reported to enhance Ca++-induced Ca++ release from the sarcoplasmic reticulum both directly and through inhibition of the enzyme phospholipid methyl transferase, influencing the phospholipid environment of the ryanodine-sensitive calcium channel. It also modulates cardiac Ca++ and Na+ through the cardiac sarcolemrnmal Na++-Ca++ exchanger and a taurine/sodium exchanger. Taurine also has antioxidant properties and reacts with a variety of potentially toxic intracellular aldehydes including acetaldehyde and malonyldialdehyde.sup.44,45.
Taurine is found in particularly high concentrations in the heart (15-25mmole/g protein) representing approximately 60% of the free amino acid pool.sup.41,46. Plasma levels are approximately 50-80mmol/L. Taurine is not an essential amino acid in humans as it can be synthesized from cysteine or methionine.sup.46 ; however, most taurine in humans is obtained directly through dietary sources, particularly from fish and milk. Biosynthetic capacity is maturation dependent, being almost non-existent in the human fetus and newborn and progressively increasing until adulthood.sup.47,48. Taurine uptake by the myocyte is an active process and b-amino acids such as beta-alanine share the transport site; it is saturable at taurine concentrations of 200 mmole.sup.46,48. In the heart the transport of taurine, like that of carnitine, can be stimulated by beta-adrenergic agonists or dibutyryl-c-AMP; however, in other tissues the c-GMP pathways seem to be important.sup.46. The taurine transporter of all tissues is regulated by the activation of two calcium sensitive enzymes: protein kinase C (which inhibits the transporter) or calmodulin (which stimulates transport).sup.48. This reciprocal regulation of intracellular taurine levels by these two enzymes is consistent with a physiologic role for taurine in the maintenance of intracellular calcium homeostasis.
The observation that TNF-.alpha. levels.sup.49 and soluble TNF receptors.sup.50,51 are raised in heart failure suggest increased cytokine activity in this condition. Grimble.sup.52 has shown that the requirement for sulfur containing amino acids is increased when TNF-.alpha. is infused. Of greater significance is the fact that transsulfuration of dietary methionine to cysteine is reduced and in consequence levels of taurine and lung glutathione fall unless the animals are supplemented with cysteine. These findings suggest that with increased cytokine activity as observed by us.sup.51 in severe heart failure, the need for cysteine and taurine will increase. Since cysteine will replenish not only taurine but also glutathione (an important endogenous antioxidant--see `Oxidative Stress` section, below), it may be an important supplement for replenishing both.
Taurine Levels and Taurine Supplementation in Heart Failure.
Cardiac taurine concentrations are altered in heart disease. Cats have very little taurine biosynthetic capacity and may exhibit a taurine deficient cardiomyopathy.sup.53. Prolonged taurine depletion of the myocardium has been shown to decrease contractile force through reduction of myofibrils.sup.54. This finding is of interest because increased calcium levels in the myocyte can activate calcium dependant proteinases that in turn can lead to the breakdown and loss of myofibils.sup.54. Taurine depletion also renders the heart more susceptible to ischemic injury.sup.55. In this context it should be noted that myocardial taurine depletion has been reported following acute ischemic injury.sup.56 and cardiovascular bypass surgery.sup.57.
In species other than the cat, myocardial hypertrophy and failure is associated with an increase in cardiac taurine concentration.sup.41,58. In spite of this increase, orally administered taurine has been shown to have a cAMP-independent positive inotropic effect in animal models of left ventricular dysfunction.sup.41. Taurine administration has been shown significantly reduce calcium overload and myocardial damage in a variety of heart failure models including that induced by the calcium paradox, doxorubicin or isoproterenol or in hamster cardiomyopathy.sup.41,59,60,61,62 ; it also has been reported to increase the survival of rabbits with aortic regurgitation.sup.63. Taurine may have a beneficial effect on cardiac arrhythmias.sup.64 including those associated with digitalis or catecholamine excess.sup.65. Studies of taurine administration in humans have been limited. However, in patients suffering from congestive heart failure taurine, given in an oral dose of 1 gram three times per day, has been reported to be extremely well tolerated and to improve both hemodynamic state and functional capacity.sup.41,66,67.
Taurine also appears to function as an osmoregulator and neuromodulator in the brain.sup.68. In addition there is evidence that taurine modulates calcium influx and efflux in the brain, increases resistance to hypoxia and reduces seizure activity when administered intraperitoneally. In streptozotocin-induced diabetic rats taurine also appears to protect against the development of renal dysfunction.sup.45 ; cardiac studies have not been performed in this model. On the same lines taurine also protects the kidney and liver against doxorubicin (adriamycin) toxicity.sup.69.